3Qs: New clues to unlocking the genome

Last week, Nature Mag­a­zine, Genome Research and Genome Biology pub­lished 30 papers on break­through research that will change the face of genetics. After nearly a decade of searching, the Ency­clo­pedia of DNA Ele­ments (ENCODE) Con­sor­tium has assigned bio­chem­ical func­tions to 80 per­cent of the genome. Pre­vi­ously con­sid­ered "junk," the devel­op­ment adds sig­nif­i­cant insight into the impor­tance of the non­coding regions of DNA. We asked Veronica Godoy-​​Carter, assis­tant pro­fessor of biology, to explain.

What is noncoding DNA and why has it been called "junk"?

The genetic mate­rial present in all living organ­isms is DNA. It is under­stood that "coding" DNA can be "read" by the cel­lular machinery, as we read a page in a book, mostly as pro­teins (e.g., your hair and nails are made up of pro­teins). How­ever, there are sec­tions of the DNA in meta­zoans (e.g., humans) and in some uni­cel­lular organ­isms known to have no read­able code, that is, non­coding DNA. The word "junk" was used in the 14th cen­tury to denote an old or infe­rior rope. Today it is used to char­ac­terize use­less arti­cles or those of little value. Thus, when researchers started to deci­pher the linear sequence of the DNA, it became obvious that a large frac­tion of it is non­coding. There­fore, the word "junk" was used to describe such non­coding regions.

We've known for a while that noncoding DNA actually has very important physiological functions. How does this new research change or add to that understanding?

ENCODE has shown that, con­trary to pre­vious views, most of the sequences of the human genome are not use­less. Though it was pre­vi­ously known than non­coding regions were impor­tant for reg­u­la­tion, this project has demon­strated that non­coding sequences serve as a roadmap for reg­u­la­tory DNA binding pro­teins that effect expres­sion of coding regions. Pre­vious to this large-​​scale analysis, no one knew about the extent of reg­u­la­tory regions that existed in "junk" DNA, now referred to as "dark matter." For example, there are many sites that are specif­i­cally chem­i­cally mod­i­fied, per­mit­ting inhi­bi­tion or induc­tion of the DNA coding regions. Remark­ably, the reg­u­la­tion of expres­sion does not only occur in coding regions that are adja­cent to reg­u­la­tory ele­ments, as pre­vi­ously thought. In some cases, reg­u­la­tion is long range and seems to occur only when the reg­u­la­tory ele­ments are near coding regions in the three-​​dimensional space!

How will this new understanding of noncoding DNA change the face of genetic research?

The long-​​range reg­u­la­tion of coding regions in the DNA is such an exciting finding because it will permit us to start under­standing the effect of known changes in the DNA sequence (i.e., muta­tions) between, say, healthy and cancer tis­sues. As it turns out, many muta­tions asso­ci­ated with dis­ease are in non­coding regions, which pre­vi­ously made little sense. Now it will be pos­sible to map muta­tions on this roadmap and impor­tantly it will be pos­sible to under­stand how muta­tions far away in the linear DNA change the reg­u­la­tory land­scape of cells.